Application of MSCs therapy in COVID-19

The year 2019 ended with the official report of an unknown pneumonia outbreak in Wuhan, Hubei Province, China. Subsequently, this novel pneumonia was named COVID-19, which mainly attacks the respiratory system, causing severe damage. Although vaccination has relieved the stress of combating pandemics around the world after one year, there are still unknowns and challenges that come with hope. In this regard, stem cell therapy has been proposed as an effective approach to treating COVID-19. Mesenchymal stem cells (MSCs) can potentially be used as a hopeful tool in the cell-based therapy due to their ability to regenerate and regulate immune response. Although research and clinical results have shown encouraging achievement in patients who were treated with MSCs, drawbacks and challenges still exist in the face of new opportunities. This review aims to introduce the challenges of the COVID-19 vaccine and the possible clinical use of MSC-based therapy. Through analysis of COVID-19 and MSC-based therapy, the author aims to find the possibilities and feasibility of using MSCs to treat acute respiratory diseases, such as COVID. As a result, the author finds that MSC treatment is very practical, and it shows significant potential to treat COVID-19. © 2023 SPIE.

Pooled evidence from preclinical and clinical studies for stem cell-based therapy in ARDS and COVID-19.

COVID-19 has severely devastated many lives across the globe. It has been speculated that stem cell-based therapy for COVID-19 treatment could be able to subsidize the effects. In preclinical and clinical studies, stem cell-based therapy has successfully eliminated inflammatory cytokines in ALI, ARDS, and COVID-19. Clinical trials have produced a variety of promising results for validating stem cell therapy in COVID-19 patients. For instance, exosome-based therapy (ExoFlow) showed an 87% survival status, and MSC-based therapy (Mesoblast) achieved an 83% survival rate in moderate to severe COVID-19 patients. This review debates the advantages of cell-free therapy, i.e., stem cell-derived exosome-based therapies, over stem cell-based therapy. This review aims to question whether the immunomodulatory effect of stem cells differs based on their origin and also tries to find possible answers for the best stem cells for treating SARS-CoV-2 infection. The role of stem cells and their extracellular vesicles in the upregulation of regulatory immune cells, growth factors (EGF, FGF, VEGF), and anti-inflammatory cytokines (IL-6, INF-α, galectin-1, notch-1, PDL-1) that promote the tissue regeneration at the injured site. The right side of the image depicts the downregulation of inflammation-inducing immune cells, pro-inflammatory cytokines, and chemokines that could also enhance COVID-19 therapy.

Treatment of diseases through stem cell bioengineering techniques

The development of stem cell transplantation technology has opened up the possibility of curing many diseases that were difficult to treat in the past. There are ethical issues in the field of widespread clinical use of human embryonic stem cells, and tissue rejection may also occurs after transplantation. One way to solve these problems is to generate specific pluripotent stem cells directly from patient cells to study specific treatments. Induced stem cells refer to a type of cell produced by the reprogramming of human somatic cells into exogenous transcription factors, which are very similar to embryonic stem cells. Both types of cells express human pluripotent factors and embryonic stem cell surface markers, and have the potential to differentiate into 3 germ layers.The induced pluripotent stem cells can be induced to differentiate into different cells under different conditions. At present, stem cell therapy has entered the clinical trial stage in many fields, and this paper discusses the stem cell regenerative medicine in the field of cardiovascular disease, eye disease, and COVID-19. This paper is a review of the current status of stem cell treatment and the challenges it is facing. © 2023 SPIE.

Application of MSCs therapy in COVID-19

The year 2019 ended with the official report of an unknown pneumonia outbreak in Wuhan, Hubei Province, China. Subsequently, this novel pneumonia was named COVID-19, which mainly attacks the respiratory system, causing severe damage. Although vaccination has relieved the stress of combating pandemics around the world after one year, there are still unknowns and challenges that come with hope. In this regard, stem cell therapy has been proposed as an effective approach to treating COVID-19. Mesenchymal stem cells (MSCs) can potentially be used as a hopeful tool in the cell-based therapy due to their ability to regenerate and regulate immune response. Although research and clinical results have shown encouraging achievement in patients who were treated with MSCs, drawbacks and challenges still exist in the face of new opportunities. This review aims to introduce the challenges of the COVID-19 vaccine and the possible clinical use of MSC-based therapy. Through analysis of COVID-19 and MSC-based therapy, the author aims to find the possibilities and feasibility of using MSCs to treat acute respiratory diseases, such as COVID. As a result, the author finds that MSC treatment is very practical, and it shows significant potential to treat COVID-19. © 2023 SPIE.

The Role of Advanced Technologies against COVID-19: Prevention, Detection, and Treatments.

Concurrent with the global outbreak of COVID-19, the race began among scientists to generate effective therapeutics for the treatment of COVID-19. In this regard, advanced technology such as nanotechnology, cell-based therapies, tissue engineering and regenerative medicine, nerve stimulation and artificial intelligence (AI) are attractive because they can offer new solutions for the prevention, diagnosis and treatment of COVID-19. Nanotechnology can design rapid and specific tests with high sensitivity for detecting infection and synthases new drugs and vaccines based on nanomaterials to directly deliver the intended antiviral agent to the desired site in the body and also provide new surfaces that do not allow virus adhesion. Mesenchymal stem cells and exosomes secreted from them apply in regenerative medicine and regulate inflammatory responses. Cell therapy and tissue engineering are combined to repair or substitute damaged tissues or cells. Tissue engineering using biomaterials, cells, and signaling molecules can develop new therapeutic and diagnostic platforms and help scientists fight viral diseases. Nerve stimulation technology can augment body's natural ability to modulate the inflammatory response and inhibit pro-inflammatory cytokines and consequently suppress cytokine storm. People can access free online health counseling services through AI and it helps very fast for screening and diagnosis of COVID-19 patients. This study is aimed first to give brief information about COVID-19 and the epidemiology of the disease. After that, we highlight important developments in the field of advanced technologies relevant to the prevention, detection, and treatment of the current pandemic.

Menstrual Blood-Derived Mesenchymal Stem Cell Therapy for Severe COVID-19 Patients.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), was declared a global pandemic in March 2020 and resulted in more than 6 million deaths worldwide to date. Although several vaccines were produced against COVID-19 and many therapeutic protocols were developed for the management of this respiratory infection, COVID-19 pandemic has still remained an unresolved problem with the emergence of new variants of SARS-CoV-2, especially vaccine-resistant variants. Probably, end of the COVID-19 needs effective and certain treatments which were undiscovered to date. According to immunomodulatory and regenerative properties, mesenchymal stem cells (MSCs) have been considered a therapeutic approach to suppressing cytokine storm caused by SARS-CoV-2 and the treatmet of severe COVID-19. Following intravenous (IV) infusion of MSCs, cells entrap in the lung, guard alveolar epithelial cells, suppress pulmonary fibrosis and improve lung dysfunction. The human menstrual blood-derived stem cells (hMenSCs) as a novel source of MSCs are collected by noninvasive, painless, and easy way without ethical issues. MenScs are an abundant and cheap source with a high proliferation rate and differentiation ability into multiple cell lineages. Regarding immunomodulatory and anti-inflammatory properties, regenerative ability and low immunogenicity, these cells exhibit great potential in the treatment of various diseases. Some clinical trial studies have begun using MenSCs to treat severe COVID-19. According to these trials, MenSC therapy showed promising and encouraging results in treating severe COVID-19. We reviewed published clinical trials and summarized the effects of MenSC therapy on severe COVID-19 with a focus on clinical and laboratory data, immune and inflammatory factors and concluded the advantages and possible risks of this procedure.

Gut Microbiota Modulation for Therapeutic Management of Various Diseases: A New Perspective Using Stem Cell Therapy.

Dysbiosis has been linked to various diseases ranging from cardiovascular, neurologic, gastrointestinal, respiratory, and metabolic illnesses to cancer. Restoring of gut microbiota balance represents an outstanding clinical target for the management of various multidrug-resistant diseases. Preservation of gut microbial diversity and composition could also improve stem cell therapy which has now diverse clinical applications in the field of regenerative medicine. Gut microbiota modulation and stem cell therapy may be considered a highly promising field that could add up towards improvement of different diseases, increasing the outcome and efficacy of each other, through mutual interplay or interaction between both therapies. Importantly, more investigations are required to reveal the cross-talk between microbiota modulation and stem cell therapy to pave the way for the development of new therapies with enhanced therapeutic outcome. This review provides an overview of dysbiosis in various diseases and their management. It also discusses microbiota modulation via antibiotic, probiotics, prebiotics and fecal microbiota transplant, to introduce the concept of dysbiosis correction for the management of various diseases. Furthermore, we demonstrate the beneficial interactions between microbiota modulation and stem cell therapy as a way for the development of new therapies in addition to limitations and future challenges regarding the applications of these therapies.

Microbial nanobionics: future perspectives and innovative approach to nanotechnology

Microbial nanotechnology is a novel approach towards developmental nanomanufacturing. The chief organisms involved in the biosynthesis of microbial nanomaterials are bacteria and microalgae that synthesize novel nanostructures such as nanocellulose and exopolysaccharides. Current approaches to microbial nanotechnology indicate their novel applications and future recommendations in various sectors. Microbial nanotechnology has revealed promising capacities in the food industry in promoting nanodelivery of food, nanobiofarming (sustainable agriculture practices), and innovative shelf life-extending approaches for fruits and vegetables. Nanobiosensor is a next-generation approach needed in early detection and high crop yield. Nanocatalyst marks the future to the diminished pesticide and insecticide level in crops. Besides the food sector, microbial nanotechnology shows its importance in other sectors such as global infectious diseases like COVID19, reveals the current nanomedicine based development and its increasing action against CoV determining the prospects of future regional or worldwide situations through anti-viral surfaces, anti-viral PPE kits, nanomaterial-based masks, and gloves to improve performance. This chapter is based on the future research recommendations and innovative prospects of nanomaterials with microbial origin and their various applications in sectors like food, global infectious diseases (COVID19), stem cell therapy, innovative approaches of antimicrobial surface coatings, and some new areas such as dentistry. © 2023 Elsevier Inc. All rights reserved.

Use of stem cell therapy in COVID-19

Severe acute respiratory syndrome coronavirus 2 is known to cause the new coronavirus disease 2019 (COVID-19), in which many organs and systems such as the lung, heart, and immune system can be severely affected. Currently, the treatment process is generally based on supportive and palliative care. Some potential drugs are being tested for treatment. At this point, perhaps a promising treatment method for many diseases in the future seems to be stem cell therapy in recent times. Stem cell therapy in COVID-19 may be a treatment method that can play an important role, especially in resistant and severe cases. In this review, we summarized the potential mechanisms of stem cell therapy and developments in this treatment modality.

Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2.

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Applying stem cell therapy in intractable diseases: a narrative review of decades of progress and challenges.

Background and Objective: Stem cell therapy (SCT) is one of the vastly researched branches of regenerative medicine as a therapeutic tool to treat incurable diseases. With the use of human stem cells such as embryonic stem cells (ESCs), adult stem cells (ASCs) and induced pluripotent stem cells (iPSCs), stem cell therapy aims to regenerate or repair damaged tissues and congenital defects. As stem cells are able to undergo infinite self-renewal, differentiate into various types of cells and secrete protective paracrine factors, many researchers have investigated the potential of SCT in regenerative medicine. Therefore, this review aims to provide a comprehensive review on the recent application of SCT in various intractable diseases, namely, haematological diseases, neurological diseases, diabetes mellitus, retinal degenerative disorders and COVID-19 infections along with the challenges faced in the clinical translation of SCT. Methods: An extensive search was conducted on Google scholar, PubMed and Clinicaltrials.gov using related keywords. Latest articles on stem cell therapy application in selected diseases along with their challenges in clinical applications were selected. Key content and findings: In vitro and in vivo studies involving SCT are shown to be safe and efficacious in treating various diseases covered in this review. There are also a number of small-scale clinical trials that validated the positive therapeutic outcomes of SCT. Nevertheless, the effectiveness of SCT are highly variable as some SCT works best in patients with early-stage diseases while in other diseases, SCT is more likely to work in patients in late stages of illnesses. Among the challenges identified in SCT translation are uncertainty in the underlying stem cell mechanism, ethical issues, genetic instability and immune rejection. Conclusions: SCT will be a revolutionary treatment in the future that will provide hope to patients with intractable diseases. Therefore, studies ought to be done to ascertain the long-term effects of SCT while addressing the challenges faced in validating SCT for clinical use. Moreover, as there are many studies investigating the safety and efficacy of SCT, future studies should look into elucidating the regenerative and reparative capabilities of stem cells which largely remains unknown.

An insight into the molecular mechanisms of mesenchymal stem cells and their translational approaches to combat COVID-19

The COVID-19 pandemic has posed a challenge to healthcare management systems around the globe. The communicability and pathogenicity of the virus are unmatched and extensive. The most common symptoms in mild cases include cough, cold, fever, headaches, shortness of breath, while in serious cases it can lead to sepsis, multiple organ failure, and ultimately death. The management of this disease has caused extreme shortness of medical aids, hospital beds, oxygen availability, and drug availability. Even though many approaches have been tried, none of them have fully catered to the therapeutic needs against this disease. This had led to the failure of all pretested therapeutic aids and drugs and made the world almost succumb to despair. The formulation and manufacturing of vaccines are still underway, and their credibility against different mutated variants of SARS-CoV-2 is another dubious factor. Under such unpredictable circumstances, the evidenced immunomodulatory abilities of mesenchymal stem cells (MSCs) have risen to popularity. There have been several trials registered for the testing of MSC therapy against COVID-19 and they have demonstrated safety and efficacy. MSCs exhibit various molecular mechanisms which are responsible for their regenerative abilities and help in combating COVID-19. However the risk of transplanting whole cells still remains a concern due to a probability of causing emboli formation due to the high dose of cell infusion, moreover the need for repetitive doses due to viability issues with MSCs is another problematic factor. Due to this there has been a shift in the focus of therapy from whole cells toward the use of their derivative extracellular vesicles (EVs). The small size, membrane bound structure, and functionality of EVs has the potential to lead to a medical revolution and assist in combating the COVID-19 pandemic holistically. © 2022 Elsevier Inc. All rights reserved.

Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm.

Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.

Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy. AIM: To evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum. METHODS: MSCs derived from the human Wharton's Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients' macrophages were established using co-culture experiments. RESULTS: Thawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to "osteocytes", "adipocytes", and "chondrocytes", and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-ß1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs. CONCLUSION: WJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.

Mesenchymal Stem Cells in the Treatment of New Coronavirus Pandemic: A Novel Promising Therapeutic Approach.

After severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks, coronavirus disease 2019 (COVID-19) is the third coronavirus epidemic that soon turned into a pandemic. This virus causes acute respiratory syndrome in infected people. The mortality rate of SARS-CoV-2 infection will probably rise unless efficient treatments or vaccines are developed. The global funding and medical communities have started performing more than five hundred clinical examinations on a broad spectrum of repurposed drugs to acquire effective treatments. Besides, other novel treatment approaches have also recently emerged, including cellular host-directed therapies. They counteract the unwanted responses of the host immune system that led to the severe pathogenesis of SARS-CoV-2. This brief review focuses on mesenchymal stem cell (MSC) principles in treating the COVID-19. The US clinical trials database and the world health organization database for clinical trials have reported 82 clinical trials (altogether) exploring the effects of MSCs in COVID-19 treatment. MSCs also had better be tried for treating other pathogens worldwide. MSC treatment may have the potential to end the high mortality rate of COVID-19. Besides, it also limits the long-term inability of survivors.

A Brief Overview of Global Trends in MSC-Based Cell Therapy.

Human mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are important adult stem cells for regenerative medicine, largely due to their regenerative characteristics such as self-renewal, secretion of trophic factors, and the capability of inducing mesenchymal cell lineages. MSCs also possess homing and trophic properties modulating immune system, influencing microenvironment around damaged tissues and enhancing tissue repair, thus offering a broad perspective in cell-based therapies. Therefore, it is not surprising that MSCs have been the broadly used adult stem cells in clinical trials. To gain better insights into the current applications of MSCs in clinical applications, we perform a comprehensive review of reported data of MSCs clinical trials conducted globally. We summarize the biological effects and mechanisms of action of MSCs, elucidating recent clinical trials phases and findings, highlighting therapeutic effects of MSCs in several representative diseases, including neurological, musculoskeletal diseases and most recent Coronavirus infectious disease. Finally, we also highlight the challenges faced by many clinical trials and propose potential solutions to streamline the use of MSCs in routine clinical applications and regenerative medicine.

Novel and promising approaches in COVID-19 treatment. (COVID-19 dedicated issue.)

Novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe respiratory infectious disease, known as coronavirus disease-19 (COVID-19). Over the past few months, a considerable rise in the incidence rate and prevalence of COVID-19 infection have been witnessed. Considering the high disease burden and rapid spread of the COVID-19 and no effective treatment is currently existing, stem cells, engineered nanobiomaterials, natural killer cells based therapy, RNA metabolites and extracellular vesicles are promising alternatives to tackle devastating epidemic. This review spotlights the applications and potential of above-mentioned methods in the treatment of COVID-19.

Mesenchymal stem cell therapy in COVID-19 pneumonia: a prospective, randomized clinical research

Objective: Deficiencies in immune-regulatory mechanisms such as immune activation and T-regulatory cells are classically referred to as cytokine storms. Mesenchymal stem cells (MSCs) act as living anti-inflammatory cells that can rebalance cytokine/immune responses to restore balance in patients with coronavirus disease-2019 (COVID-19) acute respiratory distress syndrome by reducing the activation of T and B cells, and dendritic and natural killer cells. The aim of this study is to provide immune modulation with stem cell transplantation by reducing the damage caused and COVID-19 infection to tissues and organs. Material and Methods: In this prospective randomized single-center clinical trial, patients were divided into 3 groups: intubated without comorbidity (n = 7);intubated with comorbidity (n = 7);not intubated (n = 7). Dosage of MSCs transplantation for each group was 1 million cell/kg intravenous at days 0, 2, and 4. age, gender, APACHE II scores, procalcitonin, C-reactive protein (CRP) and leukocyte values, and cluster of difference 4 (CD4), CD8, interleukin 2 (IL-2), and IL-6 levels, morbidities, number of days in intensive care unit, mortality were recorded. Clinical results, changes in inflammatory and immune function levels, and side effects were evaluated. Each patient's improvement in oxygenation and symptoms were recorded in the days after MSC transplantation. After treatment, lymphocyte, CRP, tumor necrosis factor-a level, and IL-6 levels were recorded.